Tumor necrosis factor (TNF)-related cytokines are critical for antiviral defense, and are important for maintaining immune homeostasis during chronic infection. Cytomegalovirus (CMV, a -herpesvirus) infection is normally subclinical despite inducing a robust immune response and establishing lifelong persistence/latency, causing acute disease only if host defenses are immature or compromised. CMV accomplishes this by employing many tactics that modulate host immunity, several which target the TNF-family. We have recently identified specific proteins in both human and mouse CMV (MCMV) that inhibit the TNF-related apoptosis inducing ligand (TRAIL) death receptors (UL141 and m166, respectively). A MCMV mutant lacking m166 (MCMVm166) shows reduced early replication, suggesting TRAIL-mediated innate defenses are normally neutralized by m166 in vivo. In stark contrast, persistent replication of MCMVm166 is enhanced, indicating that viral inhibition of TRAIL DR signaling may promote adaptive immune control of chronic infection. This hypothesis is supported by our results showing that TRAIL-R2-/- mice control MCMV persistence better than wild- type mice. Our identification of specific CMV proteins that inhibit TRAIL DR has revealed new roles for this TNF-related signaling pathway in regulating the early and later phases of a herpesvirus infection. In this proposal we will determine the mechanism(s) by which TRAIL DR signaling, and m166 inhibition of this pathway, function to regulate innate and adaptive immune control of MCMV infection. The fact that both mouse and human CMV encode specific proteins that restrict expression of the TRAIL DR strongly suggests this TNF-related cytokine system regulates CMV infection in humans, and consequently these studies will provide heuristic value.